Total body irradiation models in NHPs – consideration of animal sex and provision of supportive care to advance model development

Abstract

Purpose

Harmonized animal models are an indispensable tool for the development of safe and effective medical countermeasures (MCMs) against radiation injury, and rhesus macaques (referred herein as NHPs) play a critical role in FDA approval of radiation medical countermeasures for acute and delayed radiation syndromes. Reliance on such models requires that they be well characterized, which consists, in part, of a reproducible dose to mortality response relationship (DRR). However, data describing the DRR for both male and female NHPs from the same study are scarce. Furthermore, the level of supportive care and the use of blood transfusions may shift the DRR, yet such information can be difficult to compare across publications. To address these knowledge gaps, the DRRs of two different NHP total body irradiation (TBI) models are compared in this paper, one which is reliant on the use of male animals provided blood transfusions, and the other which incorporates both sexes wherein animals are not provided transfusions.

Materials and methods

Studies were conducted using NHPs (Macacca mulatta) receiving TBI, with survival reported over a 60 days. Two primary studies, incorporating both male and female animals not receiving blood transfusions as a provision of supportive care, were compared to two previously published studies, which incorporated only male animals provided blood transfusions as a part of the supportive care regimen. Criterion for euthanasia, and all other provisions of supportive care were comparable. Linear probit plots estimating the lethal dose (LD) and upper and lower limits of the 95% confidence interval (CI) for 10, 30, 50, 70 and 90% mortality, were compared between individual studies and the two models presented.

Results

Comparison of probit estimates reveals two important findings. (1) Females have higher mortality than males at identical radiation doses, and (2) blood transfusions increased survival of male animals at lower doses but not at high doses of radiation exposure.

Conclusions

The use of single sex animal models may lead to an incomplete understanding of potential sex differences in the dose to mortality response of the TBI model. Consistent use of both sexes and type of supportive care will improve the transferability and reliability of NHP-TBI models currently in use, assist in the selection of radiation doses for single dose lethality studies, and allow investigators to determine the effectiveness of a particular MCM.

Keywords:

• Medical countermeasures against radiation (MCM)
• non-human primates (NHP)
• total body irradiation (TBI)
• dose–response relationship (DRR)

Acknowledgements

The authors like to specifically thank Dr Wieslaw Wiezbicki for radiation dosimetry support, the staff at CRL for their animal care support, and Dr Thomas MacVittie, Emeritis Professor at the University of Maryland, Baltimore, for advice and discussions concerning NHP irradiations, euthanasia criteria, and provision of supportive care.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the National Institute of Allergy and Infection Diseases contract number HHSN272201500013I, and National Institutes of Health Department of Health and Human Services under contract numbers HHS0100200800060C, HHSO100201100045C and HHSO100201000051C.

Notes on contributors

Tyler Beach

Tyler Beach, Ph.D., is a Research Scientist and Study Director at SRI International focusing on the development of animal models and medical countermeasures against radiation.

Simon Authier

Simon Authier, Ph.D., DVM, is a Senior Director of Scientific Operations and Veterinary Science at Charles River in Laval, Quebec.

Harold S. Javitz

Harold Javitz is a Senior Biostatistician at SRI International and conducts statistical analyses for toxicology and radiation studies.

Karen Wong

Karen Wong, B.S., is a Principal Scientist at the Laval site of Charles River Laboratories, Montreal. Karen has been involved with numerous toxicology, efficacy, and radiation studies in a variety of animal species as the Study Director or Supporting Scientist.

James Bakke

James Bakke, B.S., is a Research Scientist and Study Director at SRI International focusing on efficacy and safety toxicology studies and animal model development for advancement of radiation countermeasure candidates in a variety of animal species.

Janet Gahagen

Janet Gahagen, B.A., is a Study Director for toxicology and pharmacokinetic studies at SRI International and specializes in working with non-human primates.

Deborah I. Bunin

Deborah Bunin, Ph.D., is the Director of Molecular Toxicology at SRI International and conducts pre-clinical toxicology and efficacy studies of medical countermeasures against radiation.

Polly Y. Chang

Polly Chang, Ph.D., is the Senior Director of Molecular and Genetic Toxicology at SRI International. She is actively engaged in radiation biology research and product development of medical countermeasures against radiation.